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Emerging Treatment Option for Hypercholesterolemia

Azelia Brown, Mercer University College of Pharmacy

Elevated blood levels of low density lipoproteins (LDL) are stated to increase risk for atherosclerotic cardiovascular events. Statins are the reported agent of choice with proven efficacy, though variation in therapeutic response may require the use of additional therapy. [1]

Serine protease proprotein convertase subtilisin–kexin type 9 (PCSK9) is an enzyme that promotes the degradation of LDL receptors which reduces LDL re-uptake and leads to increased LDL levels. [2] Some PCSK9 agents are monoclonal antibodies that work by sequestering PCSK9 and preventing it from binding to LDL receptors. Inclisiran interferes with ribonucleic acid, reducing the hepatic production PCSK9. [3]

Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol [3]

Follow-up visits were conducted every two weeks for the first month and then every month thereafter. Fasting blood samples were conducted at each visit and end-of trial evaluations were conducted at day 210. If patient’s LDL levels were not within 20% of the starting level, follow-up was conducted every 30 days until day 360 or until LDL levels were within 20% of baseline. Adverse effects, vital signs, laboratory values, and electrocardiograms were obtained at follow-up visits.

Duration

1 year

Primary Outcome Measure

Percentage change from baseline in LDL cholesterol level at day 180

Baseline Characteristics

Single dose regimens

Two dose regimens

Placebo

200 mg

300 mg

500 mg

Placebo

100 mg

200 mg

300 mg

Mean age, years ± SD

62 ± 11.4

63.9 ± 10.8

63.9 ± 12.8

62.1 ± 12.5

62.8 ± 10.3

65.2 ± 9.4

62.3 ± 10.9

64.1 ± 9.4

Male, %

65

65

67

71

53

62

63

74

White, %

92

90

90

95

94

92

97

95

Previous ASCVD, %

69

72

77

55

74

69

65

70

Statin use, %

70

53

75

65

77

71

67

73

Cholesterol, mg/dL

Total cholesterol, average

207.7

200

201.4

218.3

208.4

207.7

219.1

221.7

LDL, average

128.5

122.8

117.8

136.9

125.2

128.5

138.8

131.3

Triglycerides, Median

125

115

134

130

137

126

127

132

Mean PCSK9, ng/dL

404.7

460.3

408.9

416.7

431.3

394.2

437.4

416.3

Results

Single dose regimens

Two dose regimens

Placebo

200 mg

300 mg

500 mg

Placebo

100 mg

200 mg

300 mg

Change in LDL, %

2.1

-27.9

-38.4

-41.9

1.8

-35.5

-44.9

-52.6

Change in total cholesterol, %

1.8

-17.6

-23.7

-26.6

0.7

-22.4

-26.8

-33.2

Change in triglycerides, %

6.4

1.1

-12.8

-12.2

-3

-6.3

0.7

-14.2

Change in PCSK9, %

2.2

-47.9

-56

-59.3

-1.2

-53.2

-66.2

-69.1

Adverse Events

Common Adverse Events: injection reactions (4% in one dose groups, 7% in two dose groups)

Targeting PCSK9 RNA, like targeting circulating PCSK9, can lead to effective LDL lowering while having a lower injection burden than other PCSK9 inhibitors. There may also be increased compliance with inclisiran over daily statin use leading to more effective cholesterol reduction. There is insufficient data to determine if the lipid reduction seen with inclisiran will result in a reduction in cardiovascular events, though some previous PCSK9 inhibitors (with different mechanisms of action) have shown to reduce major cardiovascular events. The size and duration of this trial cannot rule out less frequent side effects or determine if inclisiran improves mortality outcomes.

References

[1] Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 2015;161:161-172.